Antiviral Responses to NNRTI-Based vs. PI-Based ARV Therapy in HIV Infected Infants Who Have or Have Not Received Single Dose NVP for Prevention of Mother-to-Child Transmission of HIV (P1060)

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ClinicalTrials.gov Identifier: NCT00307151

Recruitment Status : Completed

First Posted : March 27, 2006

Results First Posted : August 3, 2011

Last Update Posted : April 13, 2017

Sponsor:

Collaborators:

National Institute of Allergy and Infectious Diseases (NIAID)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Information provided by (Responsible Party):

International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Study Description

Brief Summary:

A single dose of nevirapine (SD NVP) given to an HIV infected pregnant woman followed by a single dose to her infant has been shown to be an effective way of reducing the risk of mother-to-child transmission (MTCT) of HIV. The purpose of this study was to compare the effectiveness of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral regimen versus a protease inhibitor (PI)-based regimen in HIV infected infants who had or had not been exposed to SD NVP for prevention of MTCT.

>> A five year follow up has been added to the study.

Condition or disease	Intervention/treatment	Phase
HIV Infections	Drug: Lamivudine Drug: Lopinavir/ritonavir Drug: Nevirapine Drug: Zidovudine	Phase 2

Show Detailed Description

Study Design


Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	452 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase II, Parallel, Randomized, Clinical Trials Comparing the Responses to Initiation of NNRTI-Based Versus PI-Based Antiretroviral Therapy in HIV Infected Infants Who Have and Have Not Previously Received Single Dose Nevirapine for Prevention of Mother-to-Child HIV Transmission
Study Start Date :	December 2005
Actual Primary Completion Date :	December 2010
Actual Study Completion Date :	December 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Drug Information available for: Nevirapine

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Coh I: NVP Cohort I: Previously received single dose nevirapine (SD NVP). Randomly assigned to receive an NNRTI-based regimen.	Drug: Lamivudine 4 mg/kg twice daily Other Names: 3TC Epivir Drug: Nevirapine Initially: 4 mg/kg for 14 days, then 7 mg/kg twice daily. In protocol version 2.0, Letter of Amendment 1 (September 2007), NVP dose increased to conform with WHO guidelines to: 160 to 200 mg/m^2/dose to max 200 mg once daily for 14 days, then 160 to 200 mg/m^2/dose to max 200 mg twice daily Other Names: NVP Viramune Drug: Zidovudine 180 mg/m^2 twice daily Other Names: ZDV AZT Retrovir
Experimental: Coh I: LPV/r Cohort I: Previously received SD NVP. Randomly assigned to receive a PI-based regimen.	Drug: Lamivudine 4 mg/kg twice daily Other Names: 3TC Epivir Drug: Lopinavir/ritonavir 16/4 mg/kg twice daily for participants 2 months of age to less than 6 months of age; 12/3 mg/kg twice daily for participants at least 6 months of age and weighing less than 15 kg; 10/2.5 mg/kg twice daily for participants at least 6 months of age and weighing between 15 kg and 40kg; 400/100 mg twice daily for participants weighing more than 40 kg Other Names: LPV/r Kaletra LPV/RTV Drug: Zidovudine 180 mg/m^2 twice daily Other Names: ZDV AZT Retrovir
Experimental: Coh II: NVP Cohort II: Did not previously receive SD NVP. Randomly assigned to receive an NNRTI-based regimen	Drug: Lamivudine 4 mg/kg twice daily Other Names: 3TC Epivir Drug: Nevirapine Initially: 4 mg/kg for 14 days, then 7 mg/kg twice daily. In protocol version 2.0, Letter of Amendment 1 (September 2007), NVP dose increased to conform with WHO guidelines to: 160 to 200 mg/m^2/dose to max 200 mg once daily for 14 days, then 160 to 200 mg/m^2/dose to max 200 mg twice daily Other Names: NVP Viramune Drug: Zidovudine 180 mg/m^2 twice daily Other Names: ZDV AZT Retrovir
Experimental: Coh II: LPV/r Cohort II: Did not previously receive SD NVP. Randomly assigned to receive a PI-based regimen	Drug: Lamivudine 4 mg/kg twice daily Other Names: 3TC Epivir Drug: Lopinavir/ritonavir 16/4 mg/kg twice daily for participants 2 months of age to less than 6 months of age; 12/3 mg/kg twice daily for participants at least 6 months of age and weighing less than 15 kg; 10/2.5 mg/kg twice daily for participants at least 6 months of age and weighing between 15 kg and 40kg; 400/100 mg twice daily for participants weighing more than 40 kg Other Names: LPV/r Kaletra LPV/RTV Drug: Zidovudine 180 mg/m^2 twice daily Other Names: ZDV AZT Retrovir

Outcome Measures

Primary Outcome Measures :

Percent of Participants With Treatment Failure, Defined as a Confirmed Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment [ Time Frame: Earlier of 24 weeks or date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010) ]
Treatment failure is defined as a confirmed plasma HIV-1 RNA level that is <1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level >400 copies/mL at 24 weeks OR permanent discontinuation of the randomized NNRTI or PI component of study treatment at or prior to 24 weeks of treatment for any reason including death. Results report percent of participants reaching a treatment failure endpoint by week 24 calculated using the Kaplan-Meier method.

Secondary Outcome Measures :

Time From Randomization to Treatment Failure, Defined as Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment [ Time Frame: Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks) ]
Treatment failure is defined as a confirmed plasma HIV-1 RNA level that is <1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level >400 copies/mL at 24 weeks OR a confirmed viral rebound >4000 copies/mL after week 24 OR permanent discontinuation of the randomized NNRTI or PI component of study treatment for any reason including death.
Percent of Participants Experiencing Virologic Failure [ Time Frame: Earlier of 24 weeks or date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010) ]
Virologic failure is defined as a confirmed plasma HIV-1 RNA level that is <1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level >400 copies/mL at 24 weeks OR death on or before 24 weeks. Results report percent of participants reaching a virologic failure endpoint by week 24 calculated using the Kaplan-Meier method.
Time From Randomization to Virologic Failure [ Time Frame: Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks) ]
Virologic failure is defined as the earlier of a confirmed plasma HIV-1 RNA level that is <1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level >400 copies/mL at 24 weeks OR a confirmed viral rebound >4000 copies/mL after week 24 OR death.
Time From Start of Study Treatment to First New Grade >=3 Lab Abnormality, Sign or Symptom Occurring on Study Treatment [ Time Frame: On randomized NNRTI or PI component of study treatment and until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010) ]
Safety events include lab abnormalities, signs or symptoms of grade 3 or higher. Events were graded according to the Division of AIDS Table for Grading Severity of Adult and Pediatric Adverse Events, Version 1.0. Events defined as new if first occurrence was after initiation of study treatment or if severity increased from entry and while on the NNRTI or PI component of study treatment.
Number of Participants Developing New NRTI, NNRTI or PI-resistant Virus [ Time Frame: Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks) ]
Numbers of participants developing new NRTI, NNRTI or PI-resistant virus after reaching a virologic failure endpoint
Change in CD4 Percent From Entry to Week 48 [ Time Frame: 48 weeks if before date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010) ]
Change was calculated as CD4 percent at week 48 minus entry CD4 percent (last CD4 percent before randomization date). Only subjects who reached 48 weeks of follow-up before DSMB decisions to unblind each Cohort were included in summary.
Time From Randomization to HIV-related Disease Progression or Death [ Time Frame: Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks) ]
HIV-related disease progression was defined as progression in WHO clinical stage from stage at entry or death. For subjects in WHO Stage IV at entry, disease progression was defined as death.
Time From Randomization to Death [ Time Frame: Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks) ]
Results report 2nd percentile of time from randomization to death

Eligibility Criteria

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Ages Eligible for Study:	2 Months to 36 Months (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria for All Participants:

age >=6 months to < 36 months (decreased to 2 months in protocol version 4.0)
HIV infected
Viral load greater than 5,000 copies/ml within 60 days of study entry
Treatment naive except for antiretrovirals (ARV) used to prevent MTCT (infant ARV use for <=1 week postpartum for prevention of MTCT allowed)
Eligible for treatment according to WHO pediatric algorithm (updated in protocol version 1.0, Letter of amendment (LOA)#1) and protocol version 2.0, LOA#3). Subjects with active opportunistic infections were not eligible for study participation until they had been treated and were clinically stable
Parent or legal guardian willing to provide signed informed consent

Inclusion Criteria for Cohort I:

Documentation of maternal or infant NVP exposure or a highly reliable verbal report. (Updated in protocol version 2.0, LOA#3 to require written clinic/hospital documentation of infant exposure to SD NVP)
Use of maternal ARV, including NVP, permitted during pregnancy
One or more of the following: strict formula feeding, initial infant HIV diagnosis occurring while younger than 60 days of age, or an initial AIDS-defining illness diagnosis by WHO criteria while younger than 60 days of age.

Inclusion Criteria for Cohort II:

Use of maternal ARVs, excluding NNRTIs, permitted during pregnancy
Evidence of lack of prior NVP exposure (added in protocol version 2.0, LOA#3) by review of maternal and child medical records or health card (or other written documentation) for evidence of NVP exposure to mother or infant during pregnancy, labor, and delivery. If no written documentation showing lack of NVP use was shown in these records or if these records were not available for review, then a verbal report considered to be highly reliable by the study nurse was acceptable AND one or more of the following:
1. Study subject born before single dose NVP was available for prevention of MTCT of HIV in the location of birth of study subject
  
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2. Study subject born before the biological mother's first positive HIV test
  
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3. Site staff had another reason to believe the subject had not been exposed to NVP
  
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Exclusion Criteria for All Participants:

Grade 2 or higher aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at study screening >>
Grade 3 or higher laboratory toxicity at study screening >>
Received ARVs for anything other than the prevention of intrapartum MTCT. Infants who received ARVs after the first week of life (e.g., for the prevention of MTCT of HIV through breastfeeding) were excluded
Acute serious infections requiring active treatment. Subjects could be receiving treatment for active TB if it did not include rifamycin drugs
Receiving chemotherapy for an active tumor >>
History of a cardiac conduction abnormality and underlying structural heart disease
Required certain medications

Exclusion Criteria for Cohort I:

History of or currently breastfeeding. Breastfed infants with a positive HIV test or who had experienced an AIDS-defining illness by WHO criteria at 60 days of age or younger were not excluded

Exclusion Criteria for Cohort II:

Exposure to any maternal NVP or other NNRTI prior to or during the pregnancy or while breastfeeding
Exposure of infant to NVP at any time including during the first week of life

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00307151

Locations


India
BJ Medical College CRS
Pune, Maharashtra, India, 411001
Malawi
University of North Carolina Lilongwe CRS
Mzimba Road, Lilongwe, Malawi
South Africa
Nelson R. Mandela School of Medicine, University of Kwazulu
Natal, Durban, South Africa, 50202
University of Stellenbosch-Tygerberg Hospital, South Africa
Cape Town, South Africa, 7700
Harriet Shezi Clinic at Chris Hani Baragwanath Hospital
Johannesburg, South Africa, 2013
Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital
Johannesburg, South Africa
Tanzania
Kilimanjaro Christian Medical CRS
IDC Research Offices, Moshi, Tanzania
Uganda
Makerere University
Kampala, Uganda
Zambia
George Clinic CRS
Lusaka, Zambia
Zimbabwe
UZ-College of Health Sciences
Harare, Zimbabwe

Sponsors and Collaborators

International Maternal Pediatric Adolescent AIDS Clinical Trials Group

National Institute of Allergy and Infectious Diseases (NIAID)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators


Study Chair:	Paul Palumbo, MD	Division of Infectious Diseases and International Health, Dartmouth-Hitchcock Medical Center
Study Chair:	Avy Violari, MD	Perinatal HIV Research Unit, University of Witwatersrand

More Information

Publications of Results:

Palumbo P, Lindsey JC, Hughes MD, Cotton MF, Bobat R, Meyers T, Bwakura-Dangarembizi M, Chi BH, Musoke P, Kamthunzi P, Schimana W, Purdue L, Eshleman SH, Abrams EJ, Millar L, Petzold E, Mofenson LM, Jean-Philippe P, Violari A. Antiretroviral treatment for children with peripartum nevirapine exposure. N Engl J Med. 2010 Oct 14;363(16):1510-20. doi: 10.1056/NEJMoa1000931.

Palumbo P, Violari A, Lindsey J, Hughes M, Jean-Philippe P, Mofenson L, Purdue L, Eshleman S for the IMPAACT P1060 Study Team. Nevirapine vs Lopinavir-ritonavir-based antiretroviral therapy in single dose Nevirapine-exposed HIV-infected infants: preliminary results from the IMPAACT P1060 Trial. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Capetown, July, 2009.

Palumbo P, Violari A, Lindsey J, Hughes M, Jean-Philippe P, Mofenson L, Bwakura-Dangarembizi M, Kamthunzi P, Eshleman S and Prudue L for the IMPAACT P1060 Team. Nevirapine (NVP)-vs. Lopinavir-Ritonavir (LPV/r)-based antiretroviral therapy (ART) among HIV-infected infants in resource-limited settings: The IMPAACT P1060 Trial. 18th Conference on Retroviruses and Opportunistic Infections, Boston, February, 2011.

Other Publications:

Arrivé E, Newell ML, Ekouevi DK, Chaix ML, Thiebaut R, Masquelier B, Leroy V, Perre PV, Rouzioux C, Dabis F; Ghent Group on HIV in Women and Children. Prevalence of resistance to nevirapine in mothers and children after single-dose exposure to prevent vertical transmission of HIV-1: a meta-analysis. Int J Epidemiol. 2007 Oct;36(5):1009-21. Epub 2007 May 28. Review.

Chi BH, Sinkala M, Stringer EM, Cantrell RA, Mtonga V, Bulterys M, Zulu I, Kankasa C, Wilfert C, Weidle PJ, Vermund SH, Stringer JS. Early clinical and immune response to NNRTI-based antiretroviral therapy among women with prior exposure to single-dose nevirapine. AIDS. 2007 May 11;21(8):957-64.

Eshleman SH, Hoover DR, Hudelson SE, Chen S, Fiscus SA, Piwowar-Manning E, Jackson JB, Kumwenda NI, Taha TE. Development of nevirapine resistance in infants is reduced by use of infant-only single-dose nevirapine plus zidovudine postexposure prophylaxis for the prevention of mother-to-child transmission of HIV-1. J Infect Dis. 2006 Feb 15;193(4):479-81. Epub 2006 Jan 11.

White PD. What causes prolonged fatigue after infectious mononucleosis: and does it tell us anything about chronic fatigue syndrome? J Infect Dis. 2007 Jul 1;196(1):4-5. Epub 2007 May 24.

Sankatsing RR, Wit FW, Pakker N, Vyankandondera J, Mmiro F, Okong P, Kastelein JJ, Lange JM, Stroes ES, Reiss P. Effects of nevirapine, compared with lamivudine, on lipids and lipoproteins in HIV-1-uninfected newborns: the stopping infection from mother-to-child via breast-feeding in Africa lipid substudy. J Infect Dis. 2007 Jul 1;196(1):15-22. Epub 2007 May 16.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Barlow-Mosha L, Angelidou K, Lindsey J, Archary M, Cotton M, Dittmer S, Fairlie L, Kabugho E, Kamthunzi P, Kinikar A, Mbengeranwa T, Msuya L, Sambo P, Patel K, Barr E, Jean-Phillipe P, Violari A, Mofenson L, Palumbo P, Chi BH. Nevirapine- Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy in HIV-Infected Infants and Young Children: Long-term Follow-up of the IMPAACT P1060 Randomized Trial. Clin Infect Dis. 2016 Oct 15;63(8):1113-1121. doi: 10.1093/cid/ciw488. Epub 2016 Jul 20.

Lindsey JC, Hughes MD, Violari A, Eshleman SH, Abrams EJ, Bwakura-Dangarembizi M, Barlow-Mosha L, Kamthunzi P, Sambo PM, Cotton MF, Moultrie H, Khadse S, Schimana W, Bobat R, Zimmer B, Petzold E, Mofenson LM, Jean-Philippe P, Palumbo P; P1060 Study Team. Predictors of virologic and clinical response to nevirapine versus lopinavir/ritonavir-based antiretroviral therapy in young children with and without prior nevirapine exposure for the prevention of mother-to-child HIV transmission. Pediatr Infect Dis J. 2014 Aug;33(8):846-54. doi: 10.1097/INF.0000000000000337.

Violari A, Lindsey JC, Hughes MD, Mujuru HA, Barlow-Mosha L, Kamthunzi P, Chi BH, Cotton MF, Moultrie H, Khadse S, Schimana W, Bobat R, Purdue L, Eshleman SH, Abrams EJ, Millar L, Petzold E, Mofenson LM, Jean-Philippe P, Palumbo P. Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. N Engl J Med. 2012 Jun 21;366(25):2380-9. doi: 10.1056/NEJMoa1113249.


Responsible Party:	International Maternal Pediatric Adolescent AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:	NCT00307151 History of Changes
Other Study ID Numbers:	IMPAACT P1060 U01AI068632 ( U.S. NIH Grant/Contract )
First Posted:	March 27, 2006 Key Record Dates
Results First Posted:	August 3, 2011
Last Update Posted:	April 13, 2017
Last Verified:	March 2017

Keywords provided by International Maternal Pediatric Adolescent AIDS Clinical Trials Group:


Treatment Naive Mother-To-Child Transmission MTCT Pediatrics Viral resistance

Additional relevant MeSH terms:


HIV Infections Lentivirus Infections Retroviridae Infections RNA Virus Infections Virus Diseases Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Immunologic Deficiency Syndromes Immune System Diseases Ritonavir Lopinavir Lamivudine Zidovudine Nevirapine HIV Protease Inhibitors	Protease Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anti-HIV Agents Anti-Retroviral Agents Antiviral Agents Anti-Infective Agents Cytochrome P-450 CYP3A Inhibitors Cytochrome P-450 Enzyme Inhibitors Reverse Transcriptase Inhibitors Nucleic Acid Synthesis Inhibitors Antimetabolites Cytochrome P-450 CYP3A Inducers Cytochrome P-450 Enzyme Inducers

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